Many brain diseases are characterized by the presence of pathological cells or abnormal extracellular structures that are highly disseminated throughout the brain tissue. This necessitates the development of nanoparticle (NP) therapeutics that can achieve similarly extensive distribution (Allard, et al., Biomaterials, 2009, 30(12), 2302-18). Convection enhanced delivery (CED) is an effective delivery strategy to circumvent the blood brain barrier (BBB) and can theoretically achieve widespread NP distribution by harnessing a pressure driven bulk flow (Allard, et al., Biomaterials, 2009, 30(12), 2302-18; Bobo, et al., Proc Natl Acad Sci U.S.A, 1994, 91(6), 2076-80; Saito and Tominaga, Neurol Med Chir (Tokyo), 2012, 52(8), 531-8). However, recent advances in technological imaging have determined that administering a nanoparticle (NP) using CED still fails to achieve therapeutically favorable distribution (Krauze, et al., Exp Neurol, 2005, 196(1), 104-11). Intracranially administered NP travel through the brain interstitium, which comprises two distinct spaces: the intercellular space (ICS) and perivascular space (PVS). NP distribution in the ICS is limited by hindrances imposed by the extracellular matrix (ECM) components (Nance, et al., Sci Transl Med, 2012, 4(149), 149ra119). Moreover, the preferable flow of NP through, and subsequent confinement within, the low resistance, fluid-filled PVS reduces their ability to reach the target cells (Krauze, et al., Exp Neurol, 2005, 196(1), 104-11; Salegio, et al., Front Neuroanat, 2014, 8, 9). These revelations have shed light on prior terminated CED-based clinical trials that failed to meet their primary and secondary outcomes (Kunwar, et al., Neuro Oncol, 2010, 12(8), 871-81; Lang, et al., Ann Neurol, 2006, 59(3), 459-66) and have spurred the development of the next generation of NP systems optimized for CED (Zhou, et al., Proc Natl Acad Sci U.S.A, 2013, 110(29), 11751-6; Yin, et al., Cancer Gene Ther, 2013, 20(6), 336-41). An improved understanding of the mechanisms that contribute to poor NP distribution following CED will enable the development of specific strategies to overcome the aforementioned barriers and maximize therapeutic NP distribution within the brain parenchyma.
Conventionally designed NP, even when delivered via the bulk flow of CED, are often found localized solely near the point of administration and cannot travel away through the ICS (Voges, et al., Ann Neurol, 2003, 54(4), 479-87). Within the ICS, components of the brain ECM, which consists of a nanoporous network of interactive structures including proteoglycans and glycosaminoglycans (Sykova and Nicholson, Physiol Rev, 2008, 88(4), 1277-340), serve as a barrier that sterically and adhesively interacts with conventional NP following administration. It has previously been demonstrated that a NP up to 114 nm in diameter, if shielded with a dense layer of polyethylene glycol (PEG), can minimize interactions with the brain ECM and rapidly diffuse within the healthy brain ICS (Nance, et al., Sci Transl Med, 2012, 4(149), 149ra119). However, relying solely on diffusion to distribute therapeutic NP throughout the ICS achieves only sub-optimal therapeutic concentrations at farther distances (Allard, et al., Biomaterials, 2009, 30(12), 2302-18).
PVS are cerebrospinal fluid (CSF) filled canals surrounding large brain vessels and are responsible for the clearance of metabolites to maintain homeostasis in the brain (Iliff, et al., Sci Transl Med, 2012, 4(147), 147ra111). PVS have been shown to play an important role in numerous neurological diseases. In Alzheimer's disease, dysregulation of the PVS glymphatic system leads to widespread development of amyloid-β plaques (Iliff, et al., Sci Transl Med, 2012, 4(147), 147ra111; Preston, et al., Neuropathol Appl Neurobiol, 2003, 29(2), 106-17). Similarly, PVS, as paths of least resistance, have been implicated in facilitating the migration of malignant gliomas throughout the brain (Cuddapah, et al., Nat Rev Neurosci, 2014, 15(7), 455-65; Baker, et al., Neoplasia, 2014, 16(7), 543-61), thereby often leading to tumor recurrence.
Hence, preferential NP trafficking through the PVS, followed by radial escape through the glia limitans and into the ICS, may be exploited to chase the propagation of neurological disease. When administered into the brain, NP encounter a higher resistance when traveling through the ICS than through the PVS (Cuddapah, et al., Nat Rev Neurosci, 2014, 15(7), 455-65); therefore, significant quantities of infused NP have been visually confirmed to traffic through PVS (Krauze, et al., Exp Neurol, 2005, 196(1), 104-11; Barua, et al., Fluids Barriers CNS, 2012, 9(1), 2). Once localized in the PVS, NPs remain sequestered due to the glia limitans, the anatomical barrier that separates the PVS and ICS (Engelhardt and Coisne, Fluids Barriers CNS, 2011, 8(1), 4). More importantly, NP accumulation and entrapment in PVS occurs following all available delivery strategies to the brain, including administrations using intranasal, intracisternal, or intrathecal routes (Salegio, et al., Front Neuroanat, 2014, 8, 9; Foley, et al., Ann Biomed Eng, 2012, 40(2), 292-303; Lochhead and Thorne, Adv Drug Deliv Rev, 2012, 64(7), 614-28). Given that NP confinement in PVS has been suggested to lead to a reduction in therapeutic efficacy in clinical trials (Barua, et al., Fluids Barriers CNS, 2012, 9(1), 2; Krauze, et al., Brain Res Brain Res Protoc, 2005, 16(1-3), 20-6), an effective strategy to reduce PVS sequestration is essential.
It is therefore an object of the present invention to provide a composition with improved brain intercellular space distribution.
It is another object of the present invention to provide shielded NPs in a hyperosmotic solution, which possess improved brain intercellular space distribution, by virtue of enhanced escape of the NPs from PVS, increased diffusion within brain ECM, or both.
It is a further object of the present invention to provide a method for delivering a composition with improved brain intercellular space distribution, by virtue of the osmotic modulation of the brain tissue in order to minimize the hindrances of the brain ECM and preferable NP accumulation in PVS.
It is another object of the present invention to provide a method for delivering shielded NPs in a hyperosmotic solution, which possess improved brain intercellular space distribution, by virtue of enhanced escape of the NPs from PVS, increased diffusion within brain ECM, or both.